Inflammatory diseases, which include inflammatory synovitis, arthritis generally, rheumatoid arthritis more specifically, and other diseases including osteoarthritis are leading causes of losses in time and earnings in the United States. More specifically, approximately six million of all arthritis sufferers are afflicted with rheumatoid arthritis. Of these, if past trends continue, over fifty percent (50% ) ultimately will have involvement of the knee joint: over eighty percent (80% ) will have involvement with the hand joint; and somewhat smaller percentages will have involvement of other joints such as the ankle, elbow, shoulder, hip and wrist.
Rheumatoid arthritis and other forms of inflammatory disease are believed to be autoimmune diseases wherein parts of the body are attacked by antibodies manufactured by the body. These antibodies may be produced in response to viruses present in the body.
A source of disability for the sufferer of rheumatoid arthritis is an inflammatory response, of unknown origin, in the synovium or lining of an afflicted joint. Chronic inflammation of synovial tissues, or synovitis, may lead to pannus formation and, eventually, to destruction of the joint cartilage. Both chronic and acute joint inflammation is generally associated with pronounced pain, which often severely restricts mobility, contact with friends and the community, and undermines the quality of life. Further sources of pain may be the presence of loose, free floating inclusions or fragments of torn synovial tissue ("loose bodies") in the synovial cavity of the joint or extraarticular inflammation in connective or muscle tissues surrounding the joint.
Most chronic joint disorders such as rheumatoid arthritis, psoriatic arthritis and osteoarthrosis are characterized by degradation of the structures in articular cartilage. Also acute inflammation of a joint is often accompanied by destruction of the cartilage, although in most cases this will not develop into the chronically destructive disease. It is not known which factors are crucial for the acutely inflamed joint to either proceed to healing or develop into the chronic process. Examples of diseases involving acute joint inflammation are yersinia arthritis, pyrophosphate arthritis, gout arthritis (arthritis urica), septic arthritis and various forms of arthritis of traumatic etiology.
Treatment with corticosteroids is one of the factors potentially conducive to the destruction of articular cartilage. Corticosteroids have been known for a long time to accelerate the degenerative process in osteoarthrosis. Such a so-called "steroid arthropathy" occurs far too often as an undesirable side effect of intra-articular corticosteroid treatment and can be avoided only by providing for a sufficiently long period of rest after the treatment. "Steroid arthropathy" is characterized by an advanced degree of articular destruction and X-ray detectable changes of the same type as occur in advanced degenerative articular disease. It should be noted however that the actual conditions prevailing in cases of arthritis with severe inflammation of the joint are of a rather more complex character, since in some of these cases injection of corticosteroids appears to have an overall positive effect on the clinical picture
Presently, the primary method of treating rheumatoid arthritis is by use of orally ingested or otherwise systemically administered compounds directed at blocking the inflammatory process. These compounds include aspirin, penicillamine, gold salts, corticosteroids and many other ethical drugs. Unfortunately, these attempts are often unsuccessful or associated with unacceptable side effects and the relief provided is temporary at best As mentioned above, some of these therapies such as corticosteroids may induce further deterioration of the joint disorder.
An alternative mode of treatment is to inject anti-inflammatory agents or substances which improve lubrication between surfaces of the joint directly into the synovial cavity of the afflicted joint, thus minimizing the risk of systemic complications.
An example of such an approach is the intra-articular injection of highly viscous or visco-elastic colloids such as high molecular weight hyaluronan (a natural constituent of synovial fluid) or its cross-linked derivatives to cushion and lubricate apposing structures within the synovial cavity. Unfortunately this treatment is not always successful and is very expensive.
Dextran is another biocompatible colloid which has been used for many years as a plasma substitute and expander following blood loss. It is not visco-elastic however and has not previously been used in the joint for treatment of local inflammation.
Dextran is a naturally occurring polysaccharide composed of chains of repeating glucose units and thus typically exists as a mixture of different size molecules whose molecular weights can range from about 300 daltons up to 15 or 20 million daltons. For most clinical purposes however, a molecular weight range of 30,000 to 110,000 daltons is preferred and the two fractions most commonly used for intravenous use have weight average molecular weights (Mw) of 40,000 and 70,000 respectively. These dextran fractions however can cause rare anaphylactic (hypersensitivity) reactions which can be prevented by blocking circulating antibodies to dextran with a very low Mw fraction of dextran (dextran 1,000).
The biological actions of dextran vary considerably with molecular weight. Some properties, such as aggregation of red blood cells by dextrans over 80,000 daltons are completely reversed by dextrans less than 35,000. The size of the molecule also determines its persistence in various body compartments such as the intravascular space or the synovial joint cavity-very small molecules like dextran 1,000 D will diffuse into surrounding tissues and the perisynovial microcirculation much faster than larger molecules such as dextran 70,000 D which have a much longer persistence in, for example, plasma or synovial fluid.
These differences in membrane permeability between very low and higher mol wt dextrans may have relevance in partly explaining the surprising effects disclosed below of different dextran fractions on pain and mobility in inflammatory joint disorders.
In summary, there exists a longfelt need for an effective solution for inflammatory joint disorders. Local administration into the joint offers the advantage of minimizing systemic side effects seen with oral or intravenous drugs. Additionally, however, the solution should provide immediate and sustained relief of pain emanating both from inflamed synovium and cartilage within the joint as well as inflamed tissue in the near vicinity of the joint. The solution should also improve joint mobility and quality of life and should be inexpensive and have a long shelf life. The present invention satisfies these needs and provides related advantages as well.